Chromone compounds

ABSTRACT

Chromone compounds having the structure ##STR1## wherein R is aryl, substituted aryl, thienyl, furyl or pyridyl, Y is hydroxy (lower) alkylene, R 1  is hydrogen, lower alkyl, aryl, substituted aryl or a heterocyclic group, R 2  is hydrogen or lower alkoxy, Y 1  is lower alkylene or hydroxyl (lower) alkylene, Z is oxygen or sulfur and R 3  is hydrogen, lower alkyl, aryl, substituted aryl, or ar(lower)alkyl have anti-allergic activity and are useful in the treatment of asthma. Compounds of the structure [I] are prepared by reacting ##STR2## wherein Y&#39; is hydroxy (lower) alkylene whose hydroxy group is optimally protected or a reactive derivative of [II] with a carboxylic acid of the formula R--COOH in the presence of a basic catalyst. The resulting compound is then reacted with an acid. Compounds of the structure [I] are prepared by reacting the compound ##STR3## with the compound X--Y 1  &#39;--Z--R 3  &#39; wherein X is an acid residue, Y&#39; is lower alkylene or hydroxy (lower) alkylene whose hydroxy group is optionally protected by a protective group, R 3  &#39; is hydrogen, lower alkyl, aryl, substituted aryl, or ar(lower)alkyl and Z is defined above. When R 3  &#39; is hydrogen, --Z--R 3  &#39; is optionally protected by a protective group. The resultant compound is subjected to an elimination reaction when Y&#39; is a protected group or when --Z--R 3  &#39; is protected to split off the protective group.

This application is a Division of Ser. No. 213,180 filed Dec. 28, 1971now U.S. Pat. No. 3,965,122 which claims the priority of JapaneseApplication Nos. 129469/1970 and 129470/1970 both filed Dec. 30, 1970.

This invention relates to new chromone compounds which possess ananti-allergic activity, process for preparing the same and a compositionthereof.

The chromone compounds can be represented by a member selected from thegroup consisting of the following general formula: ##STR4## wherein R isaryl which may have one or more possible substituents, thienyl, furyl orpyridyl and Y is hydroxy (lower) alkylene, and the following generalformula: ##STR5## wherein R₁ is hydrogen, lower alkyl or aryl which mayhave one or more possible substituents or heterocyclic group, R₂ ishydrogen or lower alkoxy, Y₁ is lower alkylene or hydroxy (lower)alkylene, Z is oxygen or sulfur and R₃ is hydrogen, lower alkyl or arylwhich may have one or more possible substituents or ar (lower) alkyl.

It has been found that the chromone compounds of the formula [I] and[I'] possess an anti-allergic activity, and may be useful in atherapeutic and precautionary treatment for asthma.

It is an object of the present invention to provide new chromonecompounds of the formula [I] and [I']. These new chromone compoundspossess anti-allergic activity and are useful as a therapeutic andprecautionary treatment for asthma. Furthermore, there may be provided apharmaceutical composition comprising, as an active ingredient, newchromone compounds of the formula [I] and/or [I'] and pharmaceuticallyacceptable carriers, as therapeutic and precautionary agents for asthma.

According to a still further feature of the invention, there areprovided processes for preparing new chromone compounds of the formula[I] and [I']. Other objects and advantageous features of the inventionwill be apparent to those conversant with the art to which the presentinvention pertains from the subsequent description.

The process of the present invention is illustrated in the followingreaction schemes: ##STR6## wherein Y' is hydroxy (lower) alkylene whosehydroxy group may be protected with possible protecting group and R andY are each as defined above. ##STR7## wherein X is acid residue, Y₁ ' islower alkylene or hydroxy(lower)alkylene whose hydroxy group may beprotected with a protecting group, R₃ ' is hydrogen, lower alkyl or arylwhich may have one or more substituents or ar(lower) alkyl and R₁, R₂,Y₁, Z and R₃ are each as defined above, provided that when R₃ ' ishydrogen, --Z--R₃ ' may be protected with a protecting group.

Suitable lower alkyl moieties in the lower alkyl and the ar(lower)alkylgroups in the above formula include, for example, a monovalent aliphatichydrocarbon having 1 to 6 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tertiary-butyl, pentyl, hexyl, cyclohexyland the like. Lower alkyl having 1 to 4 carbon atoms is preferred.

Suitable aryl moieties in the aryl and the ar(lower)-alkyl groups in theabove formula include, for example, a monovalent aromatic hydrocarbon ofnot more than 10 carbon atoms, such as phenyl, tolyl, naphthyl and thelike. The aforementioned aryl group may have one or more suitablesubstituents, for example, lower alkoxy (e.g., methoxy, ethoxy, propoxy,butoxy, isopropoxy, isobutoxy, t-butoxy, pentoxy, isopentoxy, hexyloxy,etc.), halogen (e.g., chlorine, bromine, iodine and fluorine), carboxy,esterified carboxy (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, phenyloxycarbonyl,benzyloxycarbonyl, etc.), and the like.

Suitable lower alkylene moieties in the lower alkylene and thehydroxy(lower)alkylene groups in the above formula include, for example,bi-valent aliphatic hydrocarbon having 1 to 6 carbon atoms such asmethylene, ethylene, methylethylene, propylene, butylene, ethylbutylene,pentylene, hexylene and the like. Lower alkylene having 1 to 4 carbonatoms is preferred.

Suitable lower alkoxy groups in the above formula include, for example,lower alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, tertiary-butoxy, pentoxy,hexyloxy and the like. Lower alkoxy having 1 to 4 carbon atoms ispreferred.

Suitable heterocyclic groups in the above formula include, for example,an unsaturated heteromonocyclic group containing one or more nitrogen,oxygen or sulfur atoms, (e.g., pyridyl, furyl, pyrimidinyl, ethienyl,etc.), and the like.

Suitable acid residues in the above formula include, for example, acidresidue from an acid, such as hydrochloric acid, sulfuric acid,hydrobromic acid, hydriodic acid, alkyl sulphate, toluenesulfonic acid,benzenesulfonic acid, dialkyl carbamate and the like.

Suitable possible protecting groups for the hydroxy group in the aboveformula include, for example, tetrahydropyranyl, dihydropyranyl,trimethylsilyl, triethylsilyl, tertiarybutyl, benzyl, acyl [e.g.,alkoxycarbonyl such as methoxycarbonyl and ethoxycarbonyl;haloalkoxycarbonyl such as 2-trichloroethyoxycarbonyl and2-tribromoethyoxycarbonyl; benzoyl, 2-(benzyloxycarbonyl)benzoyl, etc.],and the like.

Suitable possible protecting groups for the mercapto group in the aboveformula include, for example, tetrahydropyranyl, dihydropyranyl,trimethylsilyl, triethylsilyl, tertiarybutyl, benzyl, p-methoxybenzyl,trityl, acyl [e.g., alkoxycarbonyl such as methoxycarbonyl andethoxycarbonyl; haloalkyl such as 2-trichloroethoxycarbonyl andtribromoethoxycarbonyl; benzoyl; 2-(benzyloxycarbonyl)benzoyl;benzyloxycarbonyl; etc.], and the like.

The compound of the formula [I] can be prepared by reacting a compoundof the formula [II] with a carboxylic acid of the formula [III] or itsreactive derivative in the presence of a basic catalyst and thenreacting the resulting compound with an acid. The reaction may becarried out in an inert solvent.

One of the starting compound [II],1,3-bis(-hydroxy-2-acetylphenoxy)-2-hydroxypropane, can be prepared bythe method described in Belgian Pat. No. 678,175. Other startingcompounds [II] can be obtained in a similar manner.

Suitable reactive derivatives of the compound [III], include, forexample, the acid halide (e.g., acid chloride, the acid bromide, etc.),acid ester (e.g., methyl ester, ethyl ester, propyl ester, isopropylester, cyanomethyl ester, p-nitrophenyl ester, pentachlorophenyl ester,2,4,5-trichlorophenyl ester, etc.), and the like.

Suitable basic catalysts for the reaction, include for example, alkalimetal (e.g., lithium, sodium, potassium, etc.), metal alkoxide (e.g.,lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide,sodium propoxide, sodium isopropoxide, potassium methoxide, potassiumethoxide, calcium methoxide, magnesium methoxide, aluminium methoxide,etc.), alkali metal amide (e.g., lithium amide, sodium amide, potassiumamide, etc.), alkali metal hydride (e.g., lithium hydride, sodiumhydride, potassium hydride, etc.), Grignard reagent (e.g., ethylmagnesium bromide, isopropyl magnesium bromide, diethylamino magnesiumbromide, diisopropylaminomagnesium bromide, mesityl magnesium bromide,etc.), trityl alkali metal (e.g., trityllithium, tritylsodium,tritylpotassium, etc.), and the like.

Suitable reaction solvents include, for example, benzene, toluene,ether, alcohol, pyridine and other inert solvents. When the compound[II] or its reactive derivative is liquid, the reaction can be carriedout even without the presence of the solvent. The reaction temperatureis not particularly critical. It can range from room temperature toelevated temperature.

The resulting reaction product is then reacted with acid such as, forexample, hydriodic acid, hydrochloric acid, hydrobromic acid, aceticacid, sulfuric acid and the like. The reaction can be carried out usingtwo or more kinds of said acids at the same time and/or using a solventsuch as alcohol (e.g., methanol, ethanol, etc.), and the like. Thereaction temperature is not particularly critical. The reaction isusually carried out under warming or heating.

When the compound [II] in which Y' is hydroxyl(lower)-alkylene whosehydroxy group is protected with a protecting group is used, theprotecting group is eliminated as the reaction with the acid proceeds.

The compound of the formula [I'] can be prepared by reacting a5-hydroxychromone compound of the formula [IV] with a compound of theformula [V] and, when necessary, subjecting the resulting compound [VI]to elimination reaction to remove the protecting group.

5-hydroxy-2-methylchromone, one of the starting compound [IV], can beprepared by the method described in the Chemical Abstracts, 52, 2002c(1956) and other compounds [IV] can be obtained in a similar manner.

The reaction of the compound [IV] with the compound [V] is preferablycarried out in the presence of base such as an alkali metal hydroxide(e.g., sodium hydroxide, potassium hydroxide, etc.), an alkali earthmetal hydroxide (e.g., calcium hydroxide, magnesium hydroxide, etc.), analkali metal carbonate (e.g., sodium carbonate, potassium carbonate,etc.), an alkali earth metal carbonate (e.g., calcium carbonate,magnesium carbonate, etc.), an alkali metal hydrogen carbonate (e.g.,sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), and thelike. A mixture of more than two of the bases may be employed. Toeliminate gas, such as hydrogen chloride, which is produced in thecourse of the reaction, it is advantageous to carry out the reaction byintroduction of air or an inert gas such as nitrogen gas into thereaction vessel. This reaction may be carried out in a solvent, such asan organic solvent, e.g., dimethylformamide, dimethylsulfoxide,1-methylpiperidinone, 1-methylpyrrolidinone, etc., and other inertorganic solvents such as benzene, dioxane, n-hexane, acetone, etc. Thereaction temperature is not particularly restrictive. The reaction isusually carried out under warming or heating.

When the resultant compound [VI] has a hydroxy or mercapto group whichis protected by a protective group, the compound is subjected toelimination reaction so as to split off the protective group. Theelimination reaction is carried out according to conventional methodssuch as decomposition with an acid, catalytic reduction, etc. The choiceof the reaction depends on the nature of the protecting group to besplit off. Decomposition with an acid is one of the most frequently usedmethods. It is preferred for splitting off protective groups such astetrahydropyranyl, dihydropyranyl, trimethylsilyl, triethylsilyl,benzyloxycarbonyl, alkoxycarbonyl, 2-benzyloxycarbonyl, benzoyl,diphenylmethyl, trityl, t-butyl etc. Preferred acids includehydrofluoric acid, hydrobromic acid, hydrochloric acid, formic acid,trifluoroacetic acid, etc. The acid is selected depending on the natureof the reaction. The decomposition reaction is frequently conducted in ahydrophilic organic solvent, water or a mixture of water and ahydrophilic organic solvent. Catalytic reduction is employed to splitoff protective groups such as benzyloxycarbonyl, benzyl, substitutedbenzyl, etc. Although other catalysts may be used, palladium ispreferred. Protective groups such as halogen-substituted alkoxycarbonyland benzoyl may be split off by treatment with a heavy metal and with analcoholate, respectively.

The chromone compound of the formulas [I] and [I'] exhibit ananti-allergic activity and can be used as a drug for treatment ofasthma. The test results on some representative compounds of thisinvention are shown below.

1. Test method

Passive cutaneous anaphylaxis was produced by intravenous injection ofan antigen (eggalbumin) to rats, each group consisting of 3 animals,sensitized with reagin-like rat antisera*. Evans blue dye was injectedsimultaneously with the antigen. The test compound (200 mg/kg) was givenorally 2 hours before the administration of the antigen. The mean amountof dye in sensitized area of the test animals was compared with that ofthe control animals. Results were expressed as the percent inhibition.

2. Test result

    ______________________________________                                                           Amount of  Inhibition                                      Compound           Dye (γ)                                                                            (%)                                             ______________________________________                                        1,3-Bis(2-phenylchromon-5-                                                    yloxy)-2-hydroxypropane                                                                          1.1        81.4                                            1,3-Bis[2-(2-furyl)chromon-                                                   5-yloxy]-2-hydroxypropane                                                                        2.6        55.9                                            5-(2-Ethoxyethyloxy)-2                                                        Phenylchromone     2.7        54.3                                            Control            5.9                                                        ______________________________________                                    

Thus, the chromone compounds of the formula [I] and [I'] are useful asan anti-allergic drug.

They can be administered by the conventional methods, the conventionaltypes of unit dosages or with the conventional pharmaceutical carriersto produce an anti-allergic activity in human beings. Thus, they can beused in the form of pharmaceutical preparations, which contain thechromone compounds in admixture with a pharmaceutical organic orinorganic carrier material suitable for enteral or parenteralapplication. Oral administration by the use of tablets, capsules or inliquid form such as suspensions, solutions or emulsions, oradministration by injection are particularly advantageous. When formedinto tablets, the conventional binding and disintegrating agents used intherapeutic unit dosages can be employed. Examples of binding agentsthat may be employed include glucose, lactose, gum acacia, gelatin,mannitol, starch paste, magnesium trisilicate and talc. Examples fordisintegrating agents that may be employed include corn starch, keratin,colloidal silica and potato starch. When administered as liquids theconventional liquid carriers can be used.

The dosage or therapeutically effective quantity of the compounds [I] or[I'] for human beings can vary over wide limits, for example, from about10 to 1000 milligrams/day for an adult. The upper limit is limited onlyby the degree of effect desired and economic considerations. For oraladministration, from about 1 to 30 milligrams of the therapeutic agentper unit dosage is employed. For injection, from 1 to 10 mg of theactive ingredient per unit dosage may be employed. Of course, the dosageof the active ingredient can vary considerably since it depends on, forexample, the age of the patient and the degree of therapeutic effectdesired. The term pharmaceutical carrier is intended to includenon-therapeutic materials which are conventionally used with unit dosageforms such as, for example, fillers, diluents, binders, lubricants,disintegrating agents and solvents. Of course, it is possible toadminister the active ingredient, i.e. the pure compound, without theuse of a pharmaceutical carrier.

It is desirable to administer the active ingredient with othertherapeutic agents such as, for example, a bronchodilator.

The following examples are offered only for the purpose of illustratingthe invention. They are not intended to limit the same.

EXAMPLE 1

Sodium hydride (3g) was gradually added, at room temperature and understirring to a mixture of1,3-bis(3-hydroxy-2-acetylphenoxy)-2-(2-tetrahydropyranyloxy)propan(3.0g) and ethyl benzoate (25 cc) and the stirred mixture was heated for15 hours at about 100° C. The reaction mixture was poured into ice-waterand the aqueous solution was washed with ether, and then dil.hydrochloric acid was added to the same. Yellowish percipitates wereextracted with ether, and the ether layer was washed with water, anddried. The solvent was then distilled off. The residue was dissolved ina mixture of methanol (50 cc) and conc. hydrochloric acid (5 cc), andthe mixture so obtained was refluxed for 20 minutes and concentrated.The residue was dissolved in methanol, and the methanol solution wasallowed to stand over night. Precipitates were collected by filtrationand recrystallized from a mixed solvent of chloroform and methanolwhereby colorless needles (0.7 g) of1,3-bis(2-phenylchromon-5-yloxy)-2-hydroxypropane, m.p. 218°-220° C.were obtained.

Analysis: C₃₃ H₂₄ O₇ : Calculated: C, 74.43; H 4.54. Found: C, 74.04; H4.47.

The following compounds were obtained according to a manner similar tothat of the preceding Example 1.

(1) 1,3-Bis[2-(3,4,5-trimethoxyphenyl)chromon-5-yloxy]-2-hydroxypropanetetrahydrate, m.p. 166°-167° C. was obtained by reacting1,3-bis(3-hydroxy-2-acetylphenoxy)-2-(2-tetrahydropyranyloxy)propanewith ethyl 3,4,5-trimethoxybenzoate.

(2) 1,3-Bis[2-(2-thienyl)chromon-5-yloxy]-2-hydroxypropane mono-hydrate,m.p. 187°-188° C. was obtained by reacting1,3-bis(3-hydroxy-2-acetylphenoxy)-2-(2-tetrahydropyranyloxy)propanewith ethyl thiophene-2-carboxylate.

(3) 1,3-Bis[2-(2-furyl)chromon-5-yloxy]-2-hydroxypropane hemihydrate,m.p. 224°-226° C. was obtained by reacting1,3-bis-(3-hydroxy-2-acetylphenoxy)-2-(2-tetrahydropyranyloxy)propanewith ethyl furan-2-carboxylate.

EXAMPLE 2

A solution of1,3-bis(3-hydroxy-2-acetylphenoxy)-2-(2-tetrahydropyranyloxy)propane(2.2 g) and ethyl pyridine-4-carboxylate (1.6 g) in pyridine was addeddropwise to a stirred suspension of sodium hydride (1.5 g) in drypyridine (20 cc), and the stirred mixture was heated for 1 hour at about100°-110° C. The reaction mixture was poured into water. The aqueoussolution was washed with ether twice, acidified with acetic acid andextracted with ether. The ether layer was washed in turn with water, anaqueous solution of sodium bicarbonate and water, and dried. The solventwas then distilled off. Methanol (50 cc) and hydrochloric acid (5 cc)were added to the residue and the resultant mixture was refluxed for 10minutes. Precipitates were collected by filtration and suspended inwater. The aqueous suspension was alkalized with an aqueous solution ofsodium bicarbonate. Precipitates were collected by filtration andrecrystallized from aqueous methanol whereby yellowish powder (0.8 g) of1,3-bis[2-(4-pyridyl)chromon-5-yloxy]-2-hydroxypropane dihydrate, m.p.165°-167° C. was obtained.

Analysis: C₃₁ H₂₂ O₇ N₂.2H₂ O: Calculated: C, 65.26; H, 4.59; N, 4.91.Found: C, 65.04; H, 4.65; N, 4.86.

EXAMPLE 3

A mixture of 5-hydroxy-2-phenylchromone (9.5 g), 1-phenoxy-2-bromoethane(9.3 g), anhydrous potassium carbonate (6.6 g) and dimethylformaide (100cc) was heated under stirring for 10 hours on a water-bath at 100° C.After the mixture cooled it was poured into ice-water and the aqueoussolution was extracted with chloroform. The chloroform layer was washedwith water and dried. The solvent was then distilled off. The residuewas recrystallized from ethyl acetate whereby pale brown flakes (4.5 g)of 5-(2-phenoxyethoxy)-2-phenylchromone, m.p. 196°-197° C. wereobtained.

Analysis: C₂₃ H₁₈ O₄ : Calculated: C, 77.08; H, 5.06. Found: C, 76.74;H, 5.12.

The following compounds were obtained in accordance with a mannersimilar to that of the preceding Example 3.

(1) Methyl 2-[2-(2-phenylchromon-5-yloxy)ethoxy]benzoate, m.p. 160°-161°C. was obtained by reacting 5-hydroxy-2-phenylchromone with methyl2-(2-bromoethoxy)benzoate.

(2) 5-(2-Phenoxyethoxy)-2-(2-thienyl)chromone, m.p. 173°- 174.5° C. wasobtained by reacting 5-hydroxy-2-(2-thienyl)-chromone with1-phenoxy-2-bromoethane.

(3) 5-(2-Ethoxyethoxy)-2-(2-thienyl)chromone, m.p. 111°- 113° C. wasobtained by reacting 5-hydroxy-2-(2-thienyl)-chromone with1-ethoxy-2-bromoethane.

(4) 5-(2-Phenylthioethoxy)-2-phenylchromone, m.p. 170°- 171° C. wasobtained by reacting 5-hydroxy-2-phenylchromone with1-phenylthio-2-bromoethane.

EXAMPLE 4

A mixture of 5-hydroxy-2-phenylchromone (730 mg),1-phenoxy-2-bromoethane (700 mg), anhydrous potassium carbonate (460 mg)and dimethylformamide (7 cc) was refluxed under stirring for 1.5 hourwhile nitrogen gas was bubbled therein. After the mixture cooled, it waspoured into ice-water and precipitates were collected by filtration,washed with water, dried and recrystallized from ethyl acetate wherebycrystals of 5-(2-phenoxyethoxy)-2-phenylchromone, m.p. 196°-197° C. wereobtained.

The following compounds were obtained according to a manner similar tothat to the preceding Example 4.

(1) 5-(2-Ethoxyethoxy)-2-phenylchromone, m.p. 94°-96° C. was obtained byreacting 5-hydroxy-2-phenylchromone with 1-ethoxy2-bromoethane.

(2) 5-(2-Phenoxyethoxy)-2-methylchromone, m.p. 142°-144° C. was obtainedby reacting 5-hydroxy-2-methylchromone with 1-phenoxy-2-bromoethane.

EXAMPLE 5

A mixture of 5-hydroxy-2-phenylchromone (480 mg),1-phenoxy-2-trimethylsilyloxy-3-chloropropane (1.0 g), anhydrouspotassium carbonate (300 mg) and dimethylformamide (5 cc) was heatedunder stirring for 3 hours on an oil-bath at 120° C. while nitrogen gaswas bubbled therein. After the mixture cooled, it was poured intoice-water and the aqueous solution was extracted with chloroform. Thechloroform layer was washed with water and the solvent was distilledoff. The residue was dissolved in a mixture of methanol (15 cc) andconc. hydrochloric acid (3 cc), and the mixture was refluxed for 4hours. The solvent was distilled off, and the residue was extracted withchloroform. The chloroform layer was washed in turn with water, anaqueous solution of sodium bicarbonate and water, and dried. The solventwas then distilled off. The residue was recrystallized from a mixedsolvent of benzene and petroleum ether whereby crystals (300 mg) of5-(3-phenoxy-2-hydroxypropoxy)-2-phenylchromone, m.p. 132°-133° C. wereobtained.

Analysis: C₂₄ H₂₀ O₅ : Calculated: C, 74.21; H, 5.19. Found: C, 74.31;H, 5.09.

The following compounds were obtained according to a manner similar tothat of the preceding Example 5.

(1) 5-(Hydroxyethoxy)-2-phenylchromone, m.p. 123.5°- 124.5° C. wasobtained by reacting 5-hydroxy-2-phenylchromone with1-(2-tetrahydropyranyloxy)-2-bromoethane.

(2) 5-(2-Hydroxyethoxy)-2-(2-thienyl)chromone, m.p. 160°- 161.5° C. wasobtained by reacting 5-hydroxy-2-(2-thienyl)chromone with1-(2-tetrahydropyranyloxy)-2-bromoethane.

(3) 5-(3-Ethoxy-2-hydroxypropoxy)-2-phenylchromone, m.p. 85°-86.5° C.was obtained by reacting 5-hydroxy-2-phenylchromone with1-ethoxy-2-(2-tetrahydropyranyloxy)-3-chloropropane.

EXAMPLE 6

The following compounds were obtained according to a manner similar tothose of the preceding Examples 3, 4, and 5.

(1) 2-[2-(2-Phenylchromon-5-yloxy)ethoxy]benzoic acid, m.p. 184°-185.5°C.

(2) 7-methoxy-5-(2-phenoxyethoxy)-2-phenylchromone, m.p. 156°- 157° C.

(3) 5-(2-ethylthioethoxy)-2-phenylchromone, m.p. 110°-111° C.

(4) 5-(2-benzyloxyethoxy)-2-phenylchromone, m.p. 102°-103° C.

(5) 5-(2-ethoxyethoxy)-2-(3-pyridyl)chromone, m.p. 121°-123° C.

(6) 5-(2-phenoxyethoxy)chromone, m.p. 100°-101° C.

(7) 5-(2-ethoxyethoxy)chromone, m.p. (4mmHg) 183° C.

(8) 5-(2-ethoxyethoxy)-2-(3-chlorophenyl)chromone, m.p. 127°-128.5° C.

EXAMPLE 7

A suitable formulation of tablets consists of:

    ______________________________________                                                                 Grams                                                ______________________________________                                        (1)    1,3-Bis(2-phenylchromon-5-yloxy)-2-                                           hydroxypropane          1                                              (2)    Lactose                 70                                             (3)    Starch                  5                                              (4)    Magnesium stearate      2                                              ______________________________________                                    

There are produced 100 tablets each containing 10 mg of the activeingredient.

EXAMPLE 8

A suitable formulation of tablets consists of:

    ______________________________________                                        (1)    5-(2-Ethoxyethoxy)-2-phenylchromone                                                                     2                                            (2)    Mannitol                  90                                           (3)    Starch                    6                                            (4)    Magnesium stearate        2                                            ______________________________________                                    

There are produced 100 tablets each containing 20 mg of the activeingredient.

What is claimed is:
 1. A chromone compound selected from the group consisting of ##STR8## wherein R is pyridyl or thienyl,Y is hydroxy (lower) alkylene, R₁ is pyridyl or thienyl, R₂ is hydrogen or lower alkoxy, Y₁ is lower alkylene or hydroxy (lower) alkylene, R₃ is hydrogen, lower alkyl, phenyl, carboxyphenyl, methoxycarbonyl-phenyl or benzyl, and Z is oxygen or sulfur.
 2. The compound according to claim 1 having the formula [I].
 3. The compound according to claim 1 in which R is thienyl.
 4. The compound according to claim 1 in which R is pyridyl.
 5. The compound according to claim 1 having the formula [I'].
 6. The compound according to claim 1 which is 1,3-bis[2-(2-thienyl)chromon-5-yloxy]-2-hydroxypropane mono-hydrate.
 7. The compound according to claim 1 which is 1,3-bis[2-(4-pyridyl)chromon-5-yloxy]-2-hydroxypropane dihydrate.
 8. The compound according to claim 1 which is 5-(2-phenoxyethoxy)-2-(2-thienyl)chromone.
 9. The compound according to claim 1 which is 5-(2-ethoxyethoxy)-2-(2-thienyl)chromone.
 10. The compound according to claim 1 which is 5-(2-hydroxyethoxy)-2-(2-thienyl)chromone.
 11. The compound according to claim 1 which is 5-(2-ethoxyethoxy)-2-(3-pyridyl)chromone.
 12. The compound according to claim 2 in which R is thienyl, or pyridyl and Y is 2-hydroxypropylene.
 13. The compound according to claim 5 in which R is thienyl or pyridyl, R₂ is hydrogen or methoxy, Y₁ is ethylene or hydroxypropylene, Z is oxygen or sulfur and R₃ is hydrogen, ethyl, phenyl, carboxyphenyl, methoxycarbonyl-phenyl or benzyl. 